Antibacterial Prodrugs to Overcome Bacterial Antimicrobial Resistance.

Antimicrobial resistance (AMR) is an increasingly concerning phenomenon that requires urgent attention because it poses a threat to human and animal health. Bacteria undergo continuous evolution, acquiring novel resistance mechanisms in addition to their intrinsic ones. Multidrug-resistant and extensively drug-resistant bacterial strains are rapidly emerging, and it is expected that bacterial AMR will claim the lives of 10 million people annually by 2050. Consequently, the urgent need for the development of new therapeutic agents with new modes of action is evident. The antibacterial prodrug approach, a strategy that includes drug repurposing and derivatization, integration of nanotechnology, and exploration of natural products, is highlighted in this review. Thus, this publication aims at compiling the most pertinent research in the field, spanning from 2021 to 2023, offering the reader a comprehensive insight into the AMR phenomenon and new strategies to overcome it.

Recent antibacterial carbohydrate-based prodrugs, drugs and delivery systems to overcome antimicrobial resistance.

Antimicrobial resistance is an increasing phenomenon that is threatening global health. Tuberculosis causative bacteria and several resistant and multidrug-resistant bacteria are widely spread and listed by the World Health Organization as global priorities for research and development. Hence, new antibacterial agents with new modes of action are urgently required. In this context, carbohydrate-based drugs have been extensively studied and used, presenting several benefits for therapeutical purposes. In this review, the latest efforts done in the carbohydrate-based antibacterial agents research field, reported from 2021 to 2023, are summarized. Carbohydrate-based prodrugs, drugs, and delivery systems are covered, highlighting derivatization of existing antibiotics, use of nanotechnology, and repurposing of available therapeutical agents as the most popular strategies used in antibacterial agents' development.

Alkyl deoxyglycoside-polymyxin combinations against critical priority carbapenem-resistant gram-negative bacteria.

The escalating antimicrobial resistance crisis urges the development of new antibacterial treatments with innovative mechanisms of action, particularly against the critical priority carbapenem-resistant Acinetobacter baumannii (CRAB), Pseudomonas aeruginosa (CRPA) and Enterobacteriaceae (CRE). Membrane-disrupting dodecyl deoxyglycosides have been reported for their interesting phosphatidylethanolamine-associated bactericidal activity against Gram-positive strains; however, their inability to penetrate the Gram-negative outer membrane (OM) renders them useless against the most challenging pathogens. Aiming to repurpose alkyl deoxyglycosides against Gram-negative bacteria, this study investigates the antimicrobial effects of five reference compounds with different deoxygenation patterns or anomeric configurations in combination with polymyxins as adjuvants for enhanced OM permeability. The generation of the lead 4,6-dideoxy scaffold was optimized through a simultaneous dideoxygenation step and applied to the synthesis of a novel alkyl 4,6-dideoxy C-glycoside 5, herein reported for the first time. When combined with subtherapeutic colistin concentrations, most glycosides demonstrated potent antimicrobial activity against several multidrug-resistant clinical isolates of CRAB, CRE and CRPA exhibiting distinct carbapenem resistance mechanisms, together with acceptable cytotoxicity against human HEK-293T and Caco-2 cells. The novel 4,6-dideoxy C-glycoside 5 emerged as the most promising prototype structure for further development (MIC 3.1 µg/mL when combined with colistin 0.5 µg/mL against CRPA or 0.25 µg/mL against several CRE and CRAB strains), highlighting the potential of C-glycosylation for an improved bioactive profile. This study is the first to show the potential of IM-targeting carbohydrate-based compounds for the treatment of infections caused by MDR Gram-negative pathogens of clinical importance.